SI9300065A - Process of preparing substituted steroidal derivatives of 3,5-dien-3-carboxylic acid from substituted steroidal 3-halogen-3,5-diene derivatives - Google Patents
Process of preparing substituted steroidal derivatives of 3,5-dien-3-carboxylic acid from substituted steroidal 3-halogen-3,5-diene derivatives Download PDFInfo
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- C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
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- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
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Abstract
Description
SMITHKLINE BEECHAM CORPORATIONSMITHKLINE BEECHAM CORPORATION
Postopek za pretvorbo substituiranih steroidnih 3-halogen3,5-dienskih derivatov v substituirane steroidne derivate 3,5-dien-3-karboksilne kislineProcess for the conversion of substituted steroid 3-halogen 3,5,5-diene derivatives into substituted steroid 3,5-diene-3-carboxylic acid derivatives
Predloženi izum se nanaša na izboljšan postopek za pretvorbo substituiranih steroidnih 3-halogen-3,5-dienskih derivatov v substituirane steroidne derivate 3,5-dien-3karboksilne kisline. Take spojine so opisane v US patentu št. 5,017,568 Holta in sodelavcev, izdanem 21. maja 1991, kot koristne pri inhibiranju steroidne 5-areduktaze.The present invention relates to an improved process for the conversion of substituted steroid 3-halogen-3,5-diene derivatives into substituted steroid derivatives of 3,5-diene-3-carboxylic acid. Such compounds are described in U.S. Pat. No. 5,017,568 to Holt et al., Issued May 21, 1991, as useful in inhibiting steroid 5-areductase.
Postopki za pripravo substituiranih steroidnih derivatov 3,5-dien-3-karboksilne kisline iz substituiranih steroidnih 3-halogen-3,5-dienskih intermediatov so že bili opisani. V US patentu št. 5,017,568 je opisana zlasti uporaba katalitske ali z alkillitijem posredovane karboksilacije steroidnih 3-bromo-3,5-dienskih intermediatov, da dobijo steroidne derivate 3,5-dien-3-karboksilne kisline (z dobitkom 15 %, kadar uporabijo N-butillitij). V ameriški patentni prijavi št. 07/817,179, vloženi 06. jaunarja 1992, so pokazali, da uporaba bazičnega medija, kadar je primemo, za selektivno deprotoniranje kislih vodikovih atomov bromiranega intermediata v gornji reakciji pred dodatkom dehalogenimega reagenta poveča dobitek dobljenega steroidnega derivata 3,5-dien-3-karboksiIne kisline (63 % za pripravo N-t-butilandrost-3,5-dien17/3-karboksamid-3-karboksilne kisline iz N-t-butil-androst-3,5-dien-3-bromo-17/3karboksamida). Etilmagnezijev bromid in etilmagnezijev klorid sta tam opisana kot prednostni bazi, uporabljeni pri pripravi tega bazičnega medija.Methods for the preparation of substituted steroidal derivatives of 3,5-diene-3-carboxylic acid from substituted steroidal 3-halogen-3,5-diene intermediates have already been described. In U.S. Pat. No. 5,017,568 describes, in particular, the use of catalytic or alkyllithium-mediated carboxylation of steroid 3-bromo-3,5-diene intermediates to obtain the steroid derivatives of 3,5-diene-3-carboxylic acid (in 15% yield when using N-butyllithium). In U.S. Pat. No. 07 / 817,179, filed Jan. 6, 1992, showed that the use of a basic medium, where appropriate, for the selective deprotonation of acidic hydrogen atoms of a brominated intermediate in the above reaction before the addition of the dehalogenating reagent increases the yield of the obtained steroid derivative 3,5-diene-3- carboxylic acids (63% for the preparation of Nt-butylandrost-3,5-diene17 / 3-carboxamide-3-carboxylic acid from Nt-butyl-androst-3,5-diene-3-bromo-17 / 3carboxamide). Ethylmagnesium bromide and ethylmagnesium chloride are described therein as preferred bases used in the preparation of this basic medium.
Poleg nizkega celotnega dobitka je glavna hiba teh objav, da so N-butillitij ter etilmagnezijev bromid in etilmagnezijev klorid dragi reagenti, ki znatno podražijo industrijski postopek. Nadalje je N-butillitij vnetljiv in karboksilacijsko reakcijo izvedejo pri razredčenih koncentracijah. Tako obstaja v stroki potreba po varnem, 'S' gospodarnem in zanesljivem postopku za pretvorbo substituiranih steroidnih 3-halogen-3,5-dienskih derivatov v substituirane steroidne derivate 3,5-dien-3karboksilne kisline.In addition to the low overall yield, the major drawback of these reports is that N-butyllithium and ethylmagnesium bromide and ethylmagnesium chloride are expensive reagents that significantly increase the cost of the industrial process. Furthermore, N-butyllithium is flammable and the carboxylation reaction is carried out at diluted concentrations. Thus, there is a need in the art for a safe, 'S' economical and reliable method for the conversion of substituted steroid 3-halogen-3,5-diene derivatives into substituted steroid derivatives of 3,5-diene-3 carboxylic acid.
Predloženi izum se nanaša na izboljšan postopek za pretvorbo steroidnih 3-halogen-3,5-dienskih derivatov v steroidne derivate 3,5-dien-3-karboksilne kisline.The present invention relates to an improved process for the conversion of steroid 3-halogen-3,5-diene derivatives into steroid 3,5-diene-3-carboxylic acid derivatives.
Predloženi izum se posebej nanaša na izboljšan postopek za pripravo N-t-butilandrost-3,5-dien-17j8-karboksamid-3-karboksilne kisline.The present invention specifically relates to an improved process for the preparation of N-t-butylandrost-3,5-diene-17H8-carboxamide-3-carboxylic acid.
Pri nadaljnjem vidiku izuma gre za nove intermediate, koristne v predloženem postopku.A further aspect of the invention is a novel intermediate useful in the present process.
Kot se uporablja zgoraj in povsod po preostalem opisu in zahtevkih, so ogljiki steroidnega jedra oštevilčeni in obroči označeni s črkami, kot sledi:As used above and throughout the rest of the description and claims, the carbons of the steroid core are numbered and the rings are numbered as follows:
'17'17
Xi' i A ./ \Xi 'and A ./ \
Farmacevtsko sprejemljive soli, hidrate in solvate spojin s formulo (I) tvorimo, kjer je primerno, po dobro znanih postopkih.Pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) are formed, where appropriate, by well known methods.
Če ni drugače navedeno, pomeni izraz halogen, kot se uporablja tukaj in v zahtevkih, klor, brom ali jod.Unless otherwise indicated, the term halogen as used herein and in the claims is chlorine, bromine or iodine.
Prednostno izraz halogen, kot se tukaj uporablja, pomeni brom ali jod.Preferably, the term halogen as used herein means bromine or iodine.
Predloženi izum se nanaša na postopek za pripravo spojine s formulo (I)The present invention relates to a process for the preparation of a compound of formula (I)
kjer jewhere it is
Rl (i) CONR2R3, kjer R2 in R3 vsakokrat neodvisno izberemo izmed vodika, alkil a, C3^cikloalkila in fenila; ali R2 in R3 skupaj z dušikom, na katerega sta vezana, predstavljata 5-6-členski nasičen obroč, ki ima do en drug heteroatom, izbran izmed kisika in dušika; ali (ii) deli, ki se dajo kemično pretvoriti v dele od (i), kot -Ca N, -COOH ali -COOC^alkil; ali njene farmacevtsko sprejemljive soli, hidrata ah solvata, označen s tem, da cianiramo spojino s formulo (II)R (i) CONR 2 R 3 wherein R 2 and R 3 are each independently selected from hydrogen, alkyl, a C 3 ^ cycloalkyl, and phenyl; or R 2 and R 3 together with the nitrogen to which they are attached represent a 5-6 membered saturated ring having up to one other heteroatom selected from oxygen and nitrogen; or (ii) parts that can be chemically converted to parts of (i), such as -Ca N, -COOH or -COOC1-6 alkyl; or a pharmaceutically acceptable salt thereof, hydrate ah solvate, characterized in that cyanide is a compound of formula (II)
kjer jewhere it is
R1, kot je definirano zgoraj, in jeR 1 , as defined above, is
X halogen; v prisotnosti cianirnega reagenta in primernega topila, prednostno dimetilformamida, da dobimo spojino s formulo (III)X halogen; in the presence of a cyanide reagent and a suitable solvent, preferably dimethylformamide, to give the compound of formula (III)
N=CN = C
(III) kjer je(III) where
R1, kot je definirano zgoraj, in nato umilimo spojino s formulo (III), da dobimo spojino s formulo (I), in nato v danem primeru tvorimo njeno farmacevtsko sprejemljivo sol, hidrat ali solvat.R 1 as defined above and then saponify the compound of formula (III) to give the compound of formula (I), and then optionally form a pharmaceutically acceptable salt, hydrate or solvate thereof.
Prednostno je R1, kot se uporablja v gornjem postopku:Preferably R 1 is as used in the above procedure:
(i) CONR2R3, kjer R2 in R3 vsakič neodvisno izberemo izmed vodika, C^alkila, Cj^cikloalkila in fenila; ah (ii) -Cs=N, -COOH ali -COOC^alkil.(i) CONR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and phenyl; ah (ii) -Cs = N, -COOH or -COOC ^ alkyl.
Najbolj prednostno je R1, kot se uporablja v gornjem postopku, jS-CONR2R3 kjer R2 in R3 vsakič neodvisno izberemo izmed vodika, C^alkila, C3^cikloalkila in fenila.Most preferably, R 1, as used in the above process, beta-CONR 2 R 3 wherein R 2 and R 3 are each independently selected from hydrogen, C ^ alkyl, C3 ^ cycloalkyl, and phenyl.
Spojine s formulo I obsegajo R1 ali dele, ki jih lahko kemično pretvorimo v tiste od R1 po znanih kemičnih reakcijah, kot so opisane v Derek Barton and U.D. Ollis, Comprehensive Organic Chemistrv: The Svthesis and Reactions of Organic Compounds. Pub: Pergamon Press (1979), pod pogojem, da R1 ne vključuje nobenih takih delov, zaradi katerih bi postal predloženi postopek neizvedljiv. Reakcije za pretvorbo teh delov v R1 izvedemo na produktih sintetskih poti, tukaj opisanih ali navedenih v zahtevkih, ali, kjer je primemo ali prednostno, na določenih intermediatih v teh sintetskih poteh. Na primer substituente karboksilne kisline lahko pretvorimo v karboksamid s pretvorbo v kislinski halid, nato pa z njegovo reakcijo z aminom. Estre lahko pretvorimo v kislino in obdelujemo kot zgoraj. Nitrile lahko pretvorimo v karboksamide z reakcijo z alkilimim sredstvom, kot t-butilacetatom ali t-butanolom, ob kisli katalizi.The compounds of formula I comprise R 1 or moieties that can be chemically converted to those of R 1 by known chemical reactions, as described in Derek Barton and UD Ollis, Comprehensive Organic Chemistry: The Svthesis and Reactions of Organic Compounds. Pub: Pergamon Press (1979), provided that R 1 does not include any such parts that would render the present process impracticable. The reactions for converting these moieties into R 1 are carried out on the products of the synthetic pathways described herein or mentioned in the claims, or, where appropriate or preferably, on certain intermediates in these synthetic pathways. For example, carboxylic acid substituents may be converted to the carboxamide by conversion to an acid halide and then reacted with an amine. The esters can be converted to acid and treated as above. Nitriles can be converted to carboxamides by reaction with an alkyl agent, such as t-butyl acetate or t-butanol, with acid catalysis.
Pri uporabi predloženega postopka za pripravo spojin s formulo (I) sintetiziramo nove intermediate z naslednjo formulo (IV)Using the present process for the preparation of compounds of formula (I), new intermediates of the following formula (IV) are synthesized
N=c (IV) kjer jeN = c (IV) where
R1 (i) CONR2R3, kjer R2 in R3 vsakokrat neodvisno izberemo izmed vodika,R 1 (i) CONR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen,
C1 ^alkila, C^cikloalkila in fenila; ali R2 in R3 skupaj z dušikom, na katerega sta vezana, predstavljata 5-6-členski nasičen obroč, ki ima do en drug heteroatom, izbran izmed kisika in dušika; ali (ii) deli, ki se dajo kemično pretvoriti v dele od (i), kot -C=N, -COOH aliC 1 ^ alkyl, C ^ cycloalkyl, and phenyl; or R 2 and R 3 together with the nitrogen to which they are attached represent a 5-6 membered saturated ring having up to one other heteroatom selected from oxygen and nitrogen; or (ii) parts that can be chemically converted into parts of (i), such as -C = N, -COOH, or
-COOC^alkil.-COOC ^ alkyl.
Prednostno je R1, kot se uporablja v gornji spojini s formulo (iv):Preferably R 1 is as used in the above compound of formula (iv):
(i) CONR2R3, kjer R2 in R3 vsakokrat neodvisno izberemo izmed vodika,(i) CONR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen,
Cj ^alkila, C^cikloalkila in fenila; ali (ii) -CsN, -COOH ali -COOC^alkil.C1-6 alkyl, C1-6 cycloalkyl and phenyl; or (ii) -CsN, -COOH or -COOC ^ alkyl.
Najbolj prednostno je R1, kot se uporablja v gornji spojini s formulo (IV): /J-CONR2R3, kjer R2 in R3 vsakič neodvisno izberemo izmed vodika, C^alkila,Most preferably, R 1 is as used in the above compound of formula (IV): / J-CONR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl,
C^cikloalkila in fenila.C ^ cycloalkyl and phenyl.
Predloženi postopek ima v primeijavi s citiranimi referencami več prednosti. Specifično so reagenti in pogoji, uporabljeni za pretvorbo 3-halogen-steroidnih-3,5dienov v steroidne 3,5-dien-3-karboksilne kisline, varni, poceni, lahko jih presnavljamo v visokih koncentracijah in dajejo visoke dobitke želene spojine, kar omogoča, da so ti postopki primerni za uporabo v industrijskem merilu.The present procedure has several advantages over the cited references. Specifically, the reagents and conditions used to convert 3-halogen-steroid-3,5dienes to steroidal 3,5-diene-3-carboxylic acids are safe, inexpensive, can be metabolized in high concentrations and give the high yields of the desired compound, allowing that these processes are suitable for use on an industrial scale.
Kot se uporablja tukaj in v zahtevkih, če ni drugače navedeno, pomeni C1 nalkil ravno ali razvejeno ogljikovodično verigo s Cl nogljiki.As used herein and in the claims, unless indicated otherwise, it means a C 1 n alkyl, straight or branched hydrocarbon chain with C ln carbons.
Z izrazom cianimi reagent, kot se uporablja tukaj in v zahtevkih, so mišljeni reagenti, ki so sposobni ob določenih pogojih reakcije s halogeniranim delom, da dobimo cianiran del. Prednostno ta cianiran del pripravimo z reakcijo ustreznega halogeniranega dela s cianimim reagentom v primernem topilu, kot je N,N-dimetilΝ,Ν-propilen sečnina (DMPU), Ν,Ν-dimetilformamid (DMF) ali N-metil-2pirolidinon (NMP), prednostno DMF, pri povišanih temperaturah.By the term cyan reagent, as used herein and in the claims, are meant reagents which are capable, under certain conditions, of reacting with a halogenated moiety to give a cyano moiety. Preferably, this cyanide moiety is prepared by reacting a suitable halogenated moiety with a cyanide reagent in a suitable solvent such as N, N-dimethylΝ, Ν-propylene urea (DMPU), Ν, Ν-dimethylformamide (DMF) or N-methyl-2pyrrolidinone (NMP) , preferably DMF, at elevated temperatures.
Z izrazom umiljenje, kot se uporablja tukaj in v zahtevkih, je mišljena spojina ali reagent ali vrsta reagentov, ki so sposobni reakcije z nitritom, da dobimo s karboksilno kislino substituiran del ob primernih pogojih. Prednostno ta s karboksilno kislino substituiran del pripravimo z reakcijo ustreznega cianiranega dela s hidroksidno bazo, prednostno z vodnim natrijevim hidroksidom, v primernem topilu, kot etilen glikolu, izopropil alkoholu ali etanolu, prednostno etanolu, pri povišanih temperaturah s sledečim nakisanjem.By the term saponification, as used herein and in the claims, is meant a compound or reagent or type of reagent capable of reaction with nitrite to give a carboxylic acid substituted moiety under suitable conditions. Preferably, the carboxylic acid substituted moiety is prepared by reaction of the corresponding cyanide moiety with a hydroxide base, preferably with aqueous sodium hydroxide, in a suitable solvent such as ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol, at elevated temperatures with subsequent acidification.
Z izrazom povišane temperature, kot .se uporablja tukaj in v zahtevkih, je mišljeno nad 25°C, prednostno pri temperaturah refluksa.The term "elevated temperature" as used herein and in claims is meant above 25 ° C, preferably at reflux temperatures.
Prednostno uporabljamo kot cianima sredstva za uporabo pri predloženem postopku cianidne komplekse, kot so opisani v Richard C. Larock, Comphrehensive Organic Transformations: A Guide to Functional Group Preparations. Pub: VCH Publidhrts, Inc. (1989), str. 861. Kot primer cianidnega kompleksa, kot se tukaj uporablja, je in situ so-zmes KCN, NiBr2(PPh3)2, Zn, PPh3. Drugi primeri so: Co(CN)3'4; K.N^CH)^ KCN; KCN, kat. Pd(PPh3)4; Co(CN)3-5; CuCN in NaCu (CN)2. Kot se tukaj uporablja, se izraz NaCu(CN)2 nanaša na reagent, nastal s skupnim pomešanjem CuCN in NaCN in situ.Preferably cyanide agents are used as agents for use in the present cyanide complex process as described in Richard C. Larock, A Comprehensive Organic Transformations: A Guide to Functional Group Preparations. Pub: VCH Publidhrts, Inc. (1989), p. 861. As an example of a cyanide complex as used herein, the in situ co-mixture is KCN, NiBr 2 (PPh 3 ) 2 , Zn, PPh 3 . Other examples are: Co (CN) 3 '4; KN ^ CH) ^ KCN; KCN, cat. Pd (PPh3) 4; Co (CN) 3 -5; CuCN and NaCu (CN) 2 . As used herein, the term NaCu (CN) 2 refers to a reagent formed by the combined mixing of CuCN and NaCN in situ.
Izmed gornjih cianimih kompleksov sta prednostna CuCN in NaCu(CN)2.Of the above cyanime complexes, CuCN and NaCu (CN) 2 are preferred.
Izmed gornjih cianimih kompleksov je posebno prednosten NaCu(CN)2.Of the cyanime complexes above, NaCu (CN) 2 is particularly preferred.
Prednostno ta kompleks NaCu(CN)2 pripravimo z dodatkom enega molskega ekvivalenta natrijevega cianida k bakrovemu(I) cianidu in situ.Preferably, this NaCu (CN) 2 complex is prepared by the addition of one mole equivalent of sodium cyanide to copper (I) cyanide in situ.
Z izrazom topilo ali primemo topilo, kot se uporablja tukaj in v zahtevkih, je mišljeno topilo, kot metilen klorid, etilen klorid, kloroform, etilen glikol, ogljikov tetraklorid, tetrahidrofuran (THF), etil eter, toluen, etil acetat, dimetilsulfoksid, N,N’-dimetil-N,N’-propilen sečnina, N-metil-2-pirolidinon, metanol, izopropil alkohol, dimetilformamid, voda, piridin, kinolin ali etanol.By the term solvent or a suitable solvent, as used herein and in the claims, is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, N , N'-dimethyl-N, N'-propylene urea, N-methyl-2-pyrrolidinone, methanol, isopropyl alcohol, dimethylformamide, water, pyridine, quinoline or ethanol.
Prednostno je zato postopek v smislu predloženega izuma posebno koristen za pripravo spojine s strukturo (IIIA)Preferably, therefore, the process of the present invention is particularly useful for the preparation of a compound of structure (IIIA)
(ΙΙΙΑ) in njeno pretvorbo v naslednjo spojino s strukturo (IA)(ΙΙΙΑ) and its conversion to the next compound of structure (IA)
(IA)(IA)
Ne da bi nadalje podrobneje razlagali, smatramo, da lahko strokovnjak ob uporabi prejšnjega opisa izkoristi predloženi izum v njegovem najširšem obsegu. Zato je treba naslednje primere smatrati le kot ilustrativne in ne kot omejevanje obsega predloženega izuma na kakršen koli način.Without further elaboration, it is believed that the person skilled in the art can use the foregoing invention to its fullest extent using the foregoing description. Therefore, the following examples should be considered as illustrative only and not as limiting the scope of the present invention in any way.
PRIMERIEXAMPLES
Dimetilformamid in bakrov(I) cianid sta dostopna pri Aldrich Chemical Co. (Milwaukee, WI), androst-4-en-3-on-17/3-karboksilna kislina je dostopna pri Berlichem, Inc. (Wayne, NJ).Dimethylformamide and copper (I) cyanide are available from Aldrich Chemical Co. (Milwaukee, WI), androst-4-en-3-on-17/3-carboxylic acid is available from Berlichem, Inc. (Wayne, NJ).
PRIMER 1EXAMPLE 1
N-t-butil-androst-3,5-dien-17fi-karboksamid-3-karboksilna kislina (i) N-t-butil-androst-3.5-dien-3-bromo-17/3-karboksamidN-t-butyl-androst-3,5-diene-17? -Carboxamide-3-carboxylic acid (i) N-t-butyl-androst-3,5-diene-3-bromo-17/3-carboxamide
V bučo pod atmosfero dušika šaržiramo 100 ml metilen klorida in 6,12 ml (2,5 molskih ekvivalentov) dimetilformamida. Raztopino ohladimo na 0 do 5°C in obdelamo s 6,90 ml (2,5 molskimi ekvivalenti) oksalil klorida ob vzdrževanju temperature med 0 in 10°C. Tvori se bela oborina. Po mešanju 1 uro prevajamo 50,1 g (19,6 molskih ekvivalentov) plinskega bromovodika v mehurčkih skozi raztopino ob vzdrževanju temperature med 0 in 10°C. Suspenzija postane bistra brezbarvna raztopina. Raztopino razplinimo z zmanjšanjem volumna raztopine na okoli 1/2 z vakuumsko destilacijo in dopolnitvijo na njen originalen volumen z metilenkloridom. Ta postopek koncentriranja/dopolnjevanja ponovimo. K dobljeni beli suspenziji dodamo 10,0 g (1 molski ekvivalent) androst-4-en-3-on-17/3-karboksilne kisline in zmes segrevamo do sobne temperature in mešamo 2 uri. Reakcijsko zmes zlijemo v posodo, ki vsebuje 100 ml metilenklorida in 23,1 g (10 molskih ekvivalentov) terc.butilamina ob vzdrževanju temperature med 0 in 10°C. Zmes mešamo 30 minut. Dodamo okoli 100 ml vode in dvofazno zmes filtriramo skozi blazinico celita. Organsko fazo ločimo in zmanjšamo na okoli polovico njenega volumna z vakuumsko destilacijo. Raztopino dopolnimo na njen originalni volumen z acetonom. Ta postopek koncentriranja/polnjenja še dvakrat ponovimo. Dobljeno acetonsko raztopino (okoli 300 ml) segrejemo na okoli 50° in obdelamo z okoli 100 ml vode, da oborimo produkt. Suspenzije ohladimo in produkt, N-t-butil-androst-3,5-dien-3-bromo-17/3karboksamid, izoliramo s filtriranjem in posušimo. Dobitek 89 %, tal. 181 do 183°C.Batch 100 ml of methylene chloride and 6.12 ml (2.5 molar equivalents) of dimethylformamide in a flask under a nitrogen atmosphere. The solution was cooled to 0 to 5 ° C and treated with 6.90 ml (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0 and 10 ° C. A white precipitate forms. After stirring for 1 hour, 50.1 g (19.6 mole equivalents) of the gas bromide in bubbles were bubbled through the solution while maintaining the temperature between 0 and 10 ° C. The suspension becomes a clear colorless solution. The solution is degassed by reducing the volume of the solution to about 1/2 by vacuum distillation and replenishing to its original volume with methylene chloride. We repeat this process of concentration / replenishment. To the resulting white suspension was added 10.0 g (1 molar equivalent) of androst-4-en-3-one-17/3-carboxylic acid and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into a container containing 100 ml of methylene chloride and 23.1 g (10 molar equivalents) of tert.butylamine while maintaining the temperature between 0 and 10 ° C. The mixture was stirred for 30 minutes. About 100 ml of water is added and the biphasic mixture is filtered through a pad of celite. The organic phase is separated and reduced to about half its volume by vacuum distillation. Make up to volume with acetone. We repeat this concentrating / filling process twice more. The resulting acetone solution (about 300 ml) was heated to about 50 ° and treated with about 100 ml of water to precipitate the product. The suspensions were cooled and the product, N-t-butyl-androst-3,5-diene-3-bromo-17 / 3carboxamide, was isolated by filtration and dried. Yield 89%, m.p. 181 to 183 ° C.
(ϋ) N-t-butil-androst-3,5-dien-3-ciano-17j3-karboksamid(ϋ) N-t-butyl-androst-3,5-diene-3-cyano-17β-carboxamide
Mešano zmes N-t-butil-androst-3,5-dien-3-bromo-17/3-karboksamida (50 g, 1 molski ekvivalent), bakrovega(I) cianida (11,0 g, 1,1 molski ekvivalent) in dimetilformamida (200 ml) segrevamo 3,5 ure do refluksa. Reakcijsko zmes ohladimo na 90 do 100°C in zlijemo ob mešanju v raztopino 100 ml koncentriranega vodnega amoniaka in 200 ml vode. Reakcijsko bučo splaknemo s 25 ml dimetilformamida, ki ga tudi dodamo k dolivalni raztopini. Dobljeno suspenzijo dvakrat ekstrahiramo z 200 ml-skimi deleži metilenklorida in organske ekstrakte filtriramo skozi blazinico celita. Organsko fazo izperemo s tremi 200-ml-skimi deleži 50/50 v/v koncentriranega vodnega amoniaka/vode, nato pa z dvema 200 ml-skima deležema vode. Organsko fazo koncentriramo v vakuumu na 150 ml in dodamo 250 ml etanola. Raztopino spet koncentriramo v vakuumu na 150 ml in dodamo 250 ml etanola. Raztopino koncentriramo v vakuumu do 300 ml ter za sproženje kristalizacije dodamo 30 ml vode. Dobljeno suspenzijo hladimo 2 uri pri 0 do 5°C. Trden produkt zberemo s filtriranjem in posušimo pri 65°C v vakuumu, da dobimo 37,0 g N-t-butil-androst-3,5-dien-3ciano-17/3-karboksamida kot rumene kristale z dobitkom 85 %, tal. 195 do 197°C.A mixed mixture of Nt-butyl-androst-3,5-diene-3-bromo-17/3-carboxamide (50 g, 1 molar equivalent), copper (I) cyanide (11.0 g, 1.1 molar equivalent) and of dimethylformamide (200 ml) was heated to reflux for 3.5 hours. The reaction mixture was cooled to 90-100 ° C and poured while stirring into a solution of 100 ml of concentrated aqueous ammonia and 200 ml of water. Rinse the reaction flask with 25 ml of dimethylformamide, which is also added to the topping solution. The resulting suspension was extracted twice with 200 ml portions of methylene chloride and the organic extracts filtered through a pad of celite. The organic phase is washed with three 200 ml portions of 50/50 v / v concentrated aqueous ammonia / water followed by two 200 ml portions of water. The organic phase was concentrated in vacuo to 150 ml and 250 ml of ethanol were added. The solution was again concentrated in vacuo to 150 ml and 250 ml of ethanol were added. The solution was concentrated in vacuo to 300 ml and 30 ml of water was added to initiate crystallization. The resulting suspension was cooled for 2 hours at 0 to 5 ° C. The solid was collected by filtration and dried at 65 ° C in vacuo to give 37.0 g of N-t-butyl-androst-3,5-diene-3cyano-17/3-carboxamide as yellow crystals in 85% yield, m.p. 195 to 197 ° C.
(iii) N-t-butil-androst-3,5-dien-17j3-karboksamid-3-karboksilna kislina(iii) N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid
Zmes N-t-butil-androst-3,5-dien-3-ciano-17/3-karboksamida (20,0 g, 1 molski ekvivalent), 50 %-nega vodnega natrijevega hidroksida (80 ml, 30 molskih ekvivalentov) in etanola (200 ml) segrevamo 18 ur do refluksa. Reakcijsko suspenzijo ohladimo na 50°C ter dodamo k mešani zmesi 6N klorovodikove kisline (300 ml) in metilen klorida (200 ml). Končni pH vodne faze je 1,5 do 2,0. Organsko fazo ločimo in vodno fazo ponovno ekstrahiramo z 250 ml metilen klorida. Združene organske faze mešamo z 2 g razbarvalnega oglja 1 uro in filtriramo skozi blazinico celita. Organsko fazo koncentriramo v vakuumu na 120 ml in dodamo 200 ml etilacetata. Suspenzijo spet koncentriramo v vakuumu na 120 ml in dodamo 200 ml etil acetata. Dobljeno suspenzijo koncentriramo v vakuumu do končnega volumna 120 ml in segrevamo 2 uri pri refluksu. Suspenzijo hladimo pri 0 do 5°C 2 uri in filtriramo. Trdni produkt posušimo v vakuumu pri 65°C, da dobimo 14,8 g (dobitek 71 %) N-tbutil-androst-3,5-dien-17/3-karboksamid-3-karboksilne kisline. S prekristalizacijo matičnih lužnic dobimo še 3,14 g (dobitek 15 %) produkta. Celoten dobitek za reakcijo 86 %. Tal. 250 do 251°C.Mixture of Nt-butyl-androst-3,5-diene-3-cyano-17/3-carboxamide (20.0 g, 1 molar equivalent), 50% aqueous sodium hydroxide (80 ml, 30 molar equivalents) and ethanol (200 ml) was heated to reflux for 18 hours. The reaction suspension was cooled to 50 [deg.] C. and 6N hydrochloric acid (300 ml) and methylene chloride (200 ml) were added to the mixture. The final pH of the aqueous phase is 1.5 to 2.0. The organic phase was separated and the aqueous phase was re-extracted with 250 ml of methylene chloride. The combined organic phases are stirred with 2 g of decolorized charcoal for 1 hour and filtered through a pad of celite. The organic phase was concentrated in vacuo to 120 ml and 200 ml of ethyl acetate were added. The suspension was again concentrated in vacuo to 120 ml and 200 ml of ethyl acetate were added. The resulting suspension was concentrated in vacuo to a final volume of 120 ml and heated at reflux for 2 hours. The suspension was cooled to 0 to 5 ° C for 2 hours and filtered. The solid was dried in vacuo at 65 ° C to give 14.8 g (71% yield) of N-tbutyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid. Recrystallization of the mother liquors gave another 3.14 g (15% yield) of the product. Total reaction yield 86%. Tal. 250 to 251 ° C.
PRIMER 2EXAMPLE 2
N-t-butil-androst-3,5-dien-3-ciano-17B-karboksamidN-t-butyl-androst-3,5-diene-3-cyano-17B-carboxamide
V 5-litrsko trogrlo bučo (Morton), opremljeno z mehanskih mešalom, termometrom in povratnim hladilnikom, šaržiramo 250 g N-t-butil-androst-3,5-dien-3-bromo-17/3karboksamida (pripravljenega kot v primeru 1 (i)), 55 g bakrovega(I) cianida, 29 g natrijevega cianida in 11 dimetilformamida. Reakcijsko zmes segrevamo do refluksa (152 do 153°C) vsaj 12 ur. Reakcijsko zmes počasi ohladimo na 25 do 30°C s kopeljo hladne vode in zlijemo v 11 50 %-nega vodnega amonijevega hidroksida (50/50 v/v koncentriran amoniak/voda) ob hitrem mešanju. Po mešanju 15 do 20 minut šaržiramo 11 metilenklorida in pustimo, da se dvofazni sistem loči. Faze ločimo in vodno fazo ponovno ekstrahiramo z 2 x 500 ml metilen klorida. Združeni metilen kloridni ekstrakti prehajajo skozi celitno fitrsko blazinico, da odstranimo netopne bakrove soli. Celitno blazinico izperemo s 150 ml metilen klorida. Združene metilen kloridne faze izperemo s 3 x 500 ml amonijevega hidroksida, da odstranimo zadnje sledove bakrovih soli. Organsko fazo koncentriramo z atmosfersko destilacijo, pri čemer odstranimo približno 1,5 1 metilen klorida. 600 ml-ski delež etanola šaržiramo v reaktor in nadaljujemo s koncentriranjem/nadomestitvijo metilen klorida z destiliranjem drugega 500 ml-skega deleža topila. V reaktor šaržiramo drugi 600 ml-ski delež etanola in z atmosfersko destilacijo nadaljujemo, dokler temperatura pare ne doseže 82 do 84°C. V reaktor šaržiramo 60 ml-ski delež vode in dobljeno suspenzijo hladimo pri 0 do 5°C vsaj 2 uri. Trdno snov zberemo, izperemo s 75 ml 50 %-nega vodnega alkohola in posušimo pri 60 do 65°C v vakuumu, da dobimo 191,3 g naslovne spojine. Dobitek 88 %, tal. 190 do 192°C.In a 5 liter Morton flask equipped with a mechanical stirrer, thermometer and reflux condenser, batch 250 g of Nt-butyl androst-3,5-diene-3-bromo-17 / 3carboxamide (prepared as in Example 1 (i )), 55 g copper (I) cyanide, 29 g sodium cyanide and 11 dimethylformamide. The reaction mixture was heated to reflux (152 to 153 ° C) for at least 12 hours. The reaction mixture was slowly cooled to 25 to 30 ° C with a cold water bath and poured into 11 50% aqueous ammonium hydroxide (50/50 v / v concentrated ammonia / water) with rapid stirring. After stirring for 15 to 20 minutes, batch 11 methylene chloride and allow the two-phase system to separate. The phases were separated and the aqueous phase was re-extracted with 2 x 500 ml of methylene chloride. The combined methylene chloride extracts were passed through a celite filter pad to remove insoluble copper salts. The celite pad was washed with 150 ml of methylene chloride. The combined methylene chloride phases are washed with 3 x 500 ml ammonium hydroxide to remove traces of copper salts. The organic phase was concentrated by atmospheric distillation, removing approximately 1.5 l of methylene chloride. The 600 ml portion of ethanol is charged to the reactor and the concentration / replacement of methylene chloride is continued by distillation of another 500 ml portion of solvent. A second 600 ml portion of ethanol was charged into the reactor and continued with atmospheric distillation until the vapor temperature reached 82 to 84 ° C. A 60 ml portion of water was charged into the reactor and the resulting suspension cooled to 0 to 5 ° C for at least 2 hours. The solid was collected, washed with 75 ml of 50% aqueous alcohol and dried at 60 to 65 ° C in vacuo to give 191.3 g of the title compound. Yield 88%, m.p. 190 to 192 ° C.
Medtem ko so prednostne izvedbe izuma prikazane z zgornjim, je mišljeno, da izum ni omejen na tukaj opisana natančna navodila in da je rezervirana pravica do vseh modifikacij, ki so v obsegu naslednjih zahtevkov.While preferred embodiments of the invention are exemplified by the foregoing, it is intended that the invention is not limited to the precise instructions described herein and that the right to any modifications within the scope of the following claims is reserved.
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| GB9206413D0 (en) * | 1992-03-24 | 1992-05-06 | Smithkline Beecham Corp | N-t-butyl-androst-3,5-diene-17b-carboxamide-3-carboxylic acid polymorph a |
| US5683995A (en) * | 1992-11-18 | 1997-11-04 | Smithkline Beecham Corporation | 17 substituted acyl-3-carboxy 3,5-diene steroidals as α-reductase inhibitors |
| US5641765A (en) * | 1992-11-18 | 1997-06-24 | Smithkline Beecham Corporation | 17-αand 17-βsubstituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-α-reductase |
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| JPH07505140A (en) | 1995-06-08 |
| ZA93801B (en) | 1993-11-05 |
| NO942925D0 (en) | 1994-08-05 |
| MX9300676A (en) | 1994-07-29 |
| WO1993016097A1 (en) | 1993-08-19 |
| IL104602A (en) | 1997-07-13 |
| HUT68303A (en) | 1995-06-28 |
| AU3612693A (en) | 1993-09-03 |
| FI943660A (en) | 1994-08-05 |
| BG98955A (en) | 1995-06-30 |
| NZ249382A (en) | 1996-05-28 |
| FI943660A0 (en) | 1994-08-05 |
| IL104602A0 (en) | 1993-07-08 |
| NO942925L (en) | 1994-08-08 |
| BR9305837A (en) | 1997-02-18 |
| HU9402303D0 (en) | 1994-10-28 |
| EP0643724A1 (en) | 1995-03-22 |
| AP9600790A0 (en) | 1996-04-30 |
| CN1078475A (en) | 1993-11-17 |
| RU94045824A (en) | 1996-07-10 |
| CZ188794A3 (en) | 1994-12-15 |
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| EP0643724A4 (en) | 1995-05-10 |
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